Promoter hypomethylation regulates CD133 expression in human gliomas

Tabu, Kouichi; Sasai, Ken; Kimura, Taichi; Wang, Lei; Aoyanagi, Eiko; Kohsaka, Shinji; Tanino, Mishie; Nishihara, Hiroshi; Tanaka, Shinya

doi:10.1038/cr.2008.270

Cited by 100 publications

(87 citation statements)

References 42 publications

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“…roles in the regulation of various genes (19,(40)(41)(42), which might be explained by a different cellular context of epigenetic regulation in lung cancer cell lines. Therefore, epigenetic modification may be the final determinant of CD133 expression and stem-like features.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2

Iida

Suzuki

Goitsuka³

et al. 2011

Int J Oncol

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Abstract. CD133 has been recognized as a specific cell surface marker for cancer stem cells in various tumors, although its biological functions and transcriptional regulation remain unclear. We found that the CD133 expression level was up-regulated in the lung cancer cell lines N417, H358, and A549, when these cell lines were cultured under hypoxic conditions. Among the five promoters (P1-P5) of human CD133 gene loci, P1 promoter was most strongly associated with hypoxia-induced promoter activity of CD133 gene expression. The P1 promoter possesses several cis-regulatory elements, including RUNT, GATA, ETS, OCT, SRY, and CREB-binding sites. A series of deletion and base substitution mutants of the P1 promoter revealed that OCT-and SRY-binding sites are important for hypoxia-induced promoter activity. The chromatin immunoprecipitation assay further confirmed the direct binding of Octamer biding transcription factor 3/4 (OCT4) and/or SRY-box containing gene 2 (SOX2) to the P1 promoter region of CD133 gene loci. In addition, the enhancement of both OCT4 and SOX2 expression by the α subunit of hypoxia-inducible factors (HIF1α and HIF2α) was required for hypoxia-induced CD133 expression. Knockdown of OCT4 or SOX2 expression in N417 cells with stabilized HIF1α and/or HIF2α abolished CD133P1 activity, while ectopic OCT4 or SOX2 expression triggers CD133P1 activity in the absence of HIF1α or HIF2α. Thus, in the hypoxic conditions, OCT4 and SOX2, both of which are induced by HIF1α/HIF2α . promote CD133 expression in the lung cancer cells via their direct interaction with the P1 promoter.

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Section: Discussionmentioning

confidence: 99%

Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2

Iida

Suzuki

Goitsuka³

et al. 2011

Int J Oncol

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“…Previously, it has been shown that activation of the Ras-Raf-MEK-ERK pathway results in activation of promoter 5 of the CD133 gene, thereby inducing CD133 expression (45). Therefore, mutations in K-Ras/B-Raf could result in increased CD133 expression.…”

Section: Disruption Of Mutant K-ras or Downstream Signaling Decreasesmentioning

confidence: 99%

Mutations in the Ras–Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer

Kemper

Versloot

Cameron

et al. 2012

Clinical Cancer Research

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Purpose: High expression of cancer stem cell (CSC) marker CD133 has been used as a predictor for prognosis in colorectal cancer (CRC), suggesting that enumeration of CSCs, using CD133, is predictive for disease progression. However, we showed recently that both CD133 mRNA and protein are not downregulated during differentiation of colon CSCs, pointing to an alternative reason for the prognostic value of CD133. We therefore set out to delineate the relation between CD133 expression and prognosis.Experimental Design: A CRC patient series was studied for expression of CD133 and other CSC markers by microarray and quantitative PCR analysis. In addition, several common mutations were analyzed to determine the relation with CD133 expression.Results: CD133 mRNA expression predicted relapse-free survival in our patient series, whereas several other CSC markers could not. Moreover, no correlation was found between expression of other CSC markers and CD133. Interestingly, high CD133 expression was related to mutations in K-Ras and B-Raf, and inhibition of mutant K-Ras or downstream mitogen-activated protein kinase kinase (MEK) signaling decreases CD133 expression. In addition, an activated K-Ras gene expression signature could predict CD133 expression in our patient set as well as data sets of other tumor types.Conclusion: CD133 expression is upregulated in CRC tumors that have a hyperactivated RasRaf-MEK-ERK pathway and is therefore related to mutations in K-Ras or B-Raf. As mutations in either gene have been related to poor prognosis, we conclude that CD133 expression is not indicative for CSC numbers but rather related to the mutation or activity status of the Ras-Raf pathway. Clin Cancer Res; 18(11); 3132-41. Ó2012 AACR.

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“…Moreover, CD133 promoter regions have been shown to be hypomethylated in numerous cancer cell lines and tumor samples with detectable levels of CD133 (5)(6)(7). In addition to the methylation status of the CD133 promoter, it has been shown that the Ras/extracellular signal-regulated kinase (ERK) signaling pathway is involved in activating CD133 transcription, but this was cell line-specific, suggesting that RAS/ERK activity is not the sole signaling pathway that controls CD133 transcription (8).…”

Section: Introductionmentioning

confidence: 99%

The Mixed Lineage Leukemia (MLL) Fusion–Associated Gene AF4 Promotes CD133 Transcription

2012

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The AC133 epitope has been used as a marker for both normal and cancer stem cells from multiple tissue lineages. To identify transcription factors that regulate CD133 expression, we conducted parallel large-scale RNA interference screens in Caco-2 cancer cells that endogenously express CD133 and in engineered HEK293 cells that express CD133 from a heterologous promoter. The transcription factor AF4 was identified following a comparative analysis between the two screens. We then showed that AF4 is a promoter of CD133 transcription in multiple cancer cell lines. Knockdown of AF4 resulted in a dramatic reduction in CD133 transcript levels. Importantly, a subset of pediatric acute lymphoblastic leukemias (ALL) harbor a fusion oncogene results from a chromosomal translocation that juxtaposes the mixed-lineage leukemia (MLL) gene and the AF4 gene. An investigation of the functional role of CD133 in the MLL-AF4-dependent ALL cells revealed that CD133 was required for leukemia cell survival. Together, our findings show AF4-dependent regulation of CD133 expression, which is required for the growth of ALL cells. CD133 may therefore represent a therapeutic target in a subset of cancers. Cancer Res; 72(8); 1929-34. Ó2012 AACR.

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Promoter hypomethylation regulates CD133 expression in human gliomas

Cited by 100 publications

References 42 publications

Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2

Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2

Mutations in the Ras–Raf Axis Underlie the Prognostic Value of CD133 in Colorectal Cancer

The Mixed Lineage Leukemia (MLL) Fusion–Associated Gene AF4 Promotes CD133 Transcription

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